Clopidogrel Resistance: Significance and Management
Dr. Hutter: Hello. Welcome to Conversations with Experts; I'm Dolph Hutter. Today we're talking about "Clopidogrel Resistance: Its Significance and Management." With me is Dr. Gilles Montalescot from Hopital Pitié-Salpêtrière in Paris, France; Dr. Marc Sabatine, from the TIMI group and the Brigham and Women's Hospital in Boston; and Dr. Paul Gurbel from the Sinai Hospital, Baltimore. Thank you for joining us.
Marc, I'm going to start with you: how is clopidogrel metabolized? And how does that affect its activity?
Dr. Sabatine: Clopidogrel is a prodrug and it needs to be activated through sequential oxidative steps in the liver (Slide 1). There is another pathway where esterases can take that pro-drug and inactivate it into a dead-end pathway and that accounts for about 85% of the prodrug; but the remaining 15% gets activated, typically in the liver, through cytochrome P450 enzymes to the active metabolite that then inhibits the platelets.
(Enlarge Image)
Slide 1.
Clopidogrel is Metabolized in a Two-Step Process
Dr. Hutter: All of you have been working on clopidogrel resistance. Paul, what is the specific enzyme that you guys have found to be the culprit?
Dr. Gurbel: The particular enzyme that we've investigated is the 2C19 pathway and we've looked at the effect of one genotype associated with loss of function, the star 2 (*2) genotype. There are multiple single nucleotide polymorphisms of this 2C19 enzyme. Most have been associated with loss of function; there is one associated with increased function.
Dr. Hutter: Gilles, you all have done independent studies looking at the presence or absence of this gene and whether or not it had any significance to the patient. What have the studies shown so far?
Dr. Montalescot: This *2 variant is associated with a poor response to clopidogrel and high platelet activity. What we have seen recently in three independent studies is that the carriers of these genetic variants have poor outcome compared to the noncarriers - they have more myocardial infarctions, more stent thrombosis - and clearly this is new and important in these patients being treated by clopidogrel.
Dr. Hutter: Marc, you just published one from the TIMI 38 group. And other studies have shown pretty much the same thing?
Dr. Sabatine: A total of seven studies have been either published or presented all showing very similar effects. It's worthwhile to note that for this *2 allele, about 30% of Caucasians are carriers, so... (Slide 2)
(Enlarge Image)
Slide 2.
Dr. Hutter: Thirty percent of Caucasians in Europe and America?
Dr. Sabatine: Exactly. So, it's quite prevalent. And all the studies have shown that carrying that allele is associated with a worse outcome. There are some subtle differences between the studies, but the vast majority indicate that even carrying one copy puts you at increased risk of stent thrombosis and probably mortality, although we need a larger sample size to make sure that it really has an impact on mortality.
Dr. Hutter: So, if I'm in the cath lab and somebody comes in with acute coronary syndrome, what do I do, Paul? Do I just get clopidogrel and hope that the dose is right, or how would you handle it?
Dr. Gurbel: We've advised investigations looking at personalized antiplatelet therapy. The amazing paradox in medicine we practice today is a "one size fits all" mentality. And we administer the two most important drugs, aspirin and clopidogrel, without any assessment of whether these agents are actually effective. Many years ago, we described response variability to clopidogrel in 2003 in a Circulation paper and we met a lot of resistance to this concept of resistance.
Dr. Hutter: So what would you do?
Dr. Gurbel: Right now, there are no guidelines to recommend uniform measurement of what...
Dr. Hutter: I'm asking what you would tell us to do.
Dr. Gurbel: What I would tell you is to treat patients according to the guidelines until we have definitive large-scale studies documenting the efficacy of point-of-care assessment of platelet function.
Dr. Hutter: Would you all kind of think that we ought to start getting beyond this one-size-fits-all approach somehow? What about point-of-care assays? There is a device where you can get information whether or not there is adequate platelet response to clopidogrel. It's called VerifyNow (Accumetrics, San Diego) (Slide 3) and it works within minutes. Is that not correct, Gilles?
(Enlarge Image)
Slide 3.
VerifyNow P2Y12 Point-of-Care Assay
Dr. Montalescot: Just 3 minutes to get a response, yeah.
Dr. Hutter: You make a good point, Paul, that we need some outcome studies, but in the meantime we have to make clinical decisions. And, of course, most of the guidelines are based on judgment anyhow. So, what are we to do?
Dr. Gurbel: The issue would be what do you do with the data that you have? How often will an increased dose work? For example, you have low inhibition or high in-treatment platelet reactivity on clopidogrel. What do you do with that? Where are the data that would support a higher dose of clopidogrel? We don't have those data either.
Dr. Sabatine: There are two issues there. As Paul pointed out there is platelet function testing and you can test people and find that they have a suboptimal response defined in a variety of ways. Paul has very nicely shown that you can give higher doses and that tends to move up your degree of inhibition.
Dr. Hutter: It does work in some people, right?
Dr. Gurbel: Yes, but the important point is that in some people it doesn't work and it may be associated with side effects.
Dr. Hutter: What are the side effects?
Dr. Montalescot: Potentially, bleeding and joint pain. In patients who are resistant to clopidogrel with clearly high platelet reactivity on treatment, we'll increase the dose: 2 pills, 3 pills, 4 pills a day. And we have some effect on the platelets side but we have also gastrointestinal side effects or joint pain, for example, and this is probably due to the excess of phenotype metabolizer accumulating. And this is not good. The patients do not like it, and clearly we would need something else and maybe a different drug, which is what we have.
Dr. Hutter: You guys are making a very good point. You know, "Hey, that's kind of simplistic thinking, Dolph, I mean you can't just test it and give more. It might not work, and it might cause some harm." Right? So I guess what we need are some good studies to look at that and, Gilles, you're running a study to look at that specifically?
Dr. Montalescot: Yes, the Artic study; 2,500 patients are being randomized in the cath lab at the time of stent implantation and the only condition is using the assay test (monitoring arm) or not using the test (conventional arm). (Editor's note: For information, go to http://clinicaltrials.gov/archive/NCT00827411/2009_01_21.) We test aspirin, we test clopidogrel, and we give information to the physicians.
Dr. Hutter: You allow the physician to make a decision because Paul's not sure what to do with it.
Dr. Montalescot: Yeah.
Dr. Gurbel: In my heart I'm sure what to do with it, but in practice for the general interventionalist I would say we're still in uncharted waters here. And we should be very cautious.
Dr. Hutter: I understand. So, in the study (ARCTIC) then what? You give it to the physician, what does the physician do?
Dr. Montalescot: There are recommendations. For example, in patients resistant to clopidogrel, do you use IIb/IIIa inhibitors in the cath lab because even if you reload the patient with clopidogrel you need to take some time to get this new load of clopidogrel. For aspirin (resistance) we would reload the patient with aspirin and we're testing the patients 2 weeks later...
Dr. Gurbel: There are randomized dta from one study to suggest that if you are non-responsive to clopidogrel by a point-of-care test, administration of tirofiban showed a reduction in periprocedural events (Slide 4). But this was one study, the numbers are not large, but it makes physiologic sense. The IIb/IIIa inhibitor attenuates platelet aggregation by a separate mechanism.
(Enlarge Image)
Slide 4.
3T/2R: Primary Endpoint at 48 Hours
Dr. Hutter: Just replacing an ineffective one with an effective one.
Dr. Gurbel: Right.
Dr. Sabatine: Another study has come out indicating that platelet function testing and genotyping both wind up being independent predictors of adverse outcomes.
Dr. Hutter: What about genotyping? It can be done faster and faster. Marc, what do you think?
Dr. Sabatine: There are devices now where if you have the DNA you can do the genotyping in the course of a couple of hours, but there's still not a point-of-care device that would be suitable for the cath lab.
But that may change as we get not only the variants that are important for clopidogrel metabolism, but also other medications. We give statins and potentially other medications where genotyping might be useful, so you might have a panel of SNPs that you might check in your cardiovascular patients, either when you start caring for them and/or when they get admitted to the hospital.
Dr. Hutter: Do think it might eventually be cost effective to do that?
Dr. Sabatine: The cost for genotyping in general is going down and I think that won't be an issue. Paul raises the issue, what would we do with the information? We need those studies as well to know, should we treat people differently? I think Gilles is getting genetic data in his ARCTIC Study as well, so we'll be able to combine all that.
Dr. Hutter: So Gilles, in your study, the doctor is going to decide what to do, and probably they're going to use a IIb/IIIa agent. Or is that in part of the protocol? Is that their decision?
Dr. Montalescot: That's part of this protocol, but what we see now is that things are going so fast that many cath labs are using an Accumetrics device so they can monitor patients and make decisions already. But we need a study…
Dr. Hutter: Marc and I were talking about how we need these studies in America, but we aren't set up to do it because it is not the standard of care as you point out, Paul. We've got that great study coming along and there is no reason you can't use the assay. You might say, "Well, let's go ahead and add a IIb/IIIa." Further down the road when you guys are getting all this information, what about new drugs? Are there drugs that bypass this pathway and then we don't have to worry about this?
Dr. Gurbel: The question is: does everyone need a new P2Y12 inhibitor? Or couldn't we selectively administer these drugs to the patients who have high platelet reactivity on the standard workhorse agent, clopidogrel? This raises the issue of determining optimization of therapy with the new agents. Instead of blanket therapy to sort out the patients who really need them, maybe it will be done by genotyping the patient before you choose your antiplatelet agent.
Dr. Hutter: Like they do in cancer now.
Dr. Sabatine: That's a very good analogy. Jessica Mega in our group has a paper coming out; we've done the same analysis in patients treated with prasugrel and found that the 2C19 variant does not impact the pharmacokinetics, the pharmacodynamics, or the clinical outcomes. So as we think about what drugs we might use, the genotyping may start pointing us in one direction versus the other. And there are other compounds that don't even require the CYP450 pathway.
Dr. Hutter: Is it possible that one of these drugs might come along where you don't really need genotyping because everybody responds the same way, or do you think that all patients are going to have some gene variabilities in terms of how they metabolize any particular drug?
Dr. Sabatine: I think there will be differences from drug to drug.
Dr. Gurbel: But if you look at the source of the variability to find pyridines that reside within the liver, with direct acting P2Y12 inhibitors there is no effective polymorphism in the liver. And up to this point in time we don't know of any effect of a P2Y12 polymorphism that affects thienopyridine response or direct acting inhibitor response.
Dr. Hutter: We've still got a lot to learn. Meanwhile, this is entirely independent of aspirin, isn't it? Aspirin has its own set of responders and non-responders. There are some aspirin-resistant people also. And that's another point-of-care study that is being done. What we're talking about is only clopidogrel so far, and not any other agents.
When do you think the ARCTIC study will be out?
Dr. Montalescot: We need one more year.
Dr. Hutter: And maybe we'll get some studies going in the United States in the meantime. Well, thank you all very much. It's a very up-to-date discussion and a very clinically important problem - 30% of the people. Wow! That's something.
And thank you for joining us. I'm Dolph Hutter.
Dr. Hutter: Hello. Welcome to Conversations with Experts; I'm Dolph Hutter. Today we're talking about "Clopidogrel Resistance: Its Significance and Management." With me is Dr. Gilles Montalescot from Hopital Pitié-Salpêtrière in Paris, France; Dr. Marc Sabatine, from the TIMI group and the Brigham and Women's Hospital in Boston; and Dr. Paul Gurbel from the Sinai Hospital, Baltimore. Thank you for joining us.
Marc, I'm going to start with you: how is clopidogrel metabolized? And how does that affect its activity?
Dr. Sabatine: Clopidogrel is a prodrug and it needs to be activated through sequential oxidative steps in the liver (Slide 1). There is another pathway where esterases can take that pro-drug and inactivate it into a dead-end pathway and that accounts for about 85% of the prodrug; but the remaining 15% gets activated, typically in the liver, through cytochrome P450 enzymes to the active metabolite that then inhibits the platelets.
(Enlarge Image)
Slide 1.
Clopidogrel is Metabolized in a Two-Step Process
Dr. Hutter: All of you have been working on clopidogrel resistance. Paul, what is the specific enzyme that you guys have found to be the culprit?
Dr. Gurbel: The particular enzyme that we've investigated is the 2C19 pathway and we've looked at the effect of one genotype associated with loss of function, the star 2 (*2) genotype. There are multiple single nucleotide polymorphisms of this 2C19 enzyme. Most have been associated with loss of function; there is one associated with increased function.
Dr. Hutter: Gilles, you all have done independent studies looking at the presence or absence of this gene and whether or not it had any significance to the patient. What have the studies shown so far?
Dr. Montalescot: This *2 variant is associated with a poor response to clopidogrel and high platelet activity. What we have seen recently in three independent studies is that the carriers of these genetic variants have poor outcome compared to the noncarriers - they have more myocardial infarctions, more stent thrombosis - and clearly this is new and important in these patients being treated by clopidogrel.
Dr. Hutter: Marc, you just published one from the TIMI 38 group. And other studies have shown pretty much the same thing?
Dr. Sabatine: A total of seven studies have been either published or presented all showing very similar effects. It's worthwhile to note that for this *2 allele, about 30% of Caucasians are carriers, so... (Slide 2)
(Enlarge Image)
Slide 2.
Dr. Hutter: Thirty percent of Caucasians in Europe and America?
Dr. Sabatine: Exactly. So, it's quite prevalent. And all the studies have shown that carrying that allele is associated with a worse outcome. There are some subtle differences between the studies, but the vast majority indicate that even carrying one copy puts you at increased risk of stent thrombosis and probably mortality, although we need a larger sample size to make sure that it really has an impact on mortality.
Dr. Hutter: So, if I'm in the cath lab and somebody comes in with acute coronary syndrome, what do I do, Paul? Do I just get clopidogrel and hope that the dose is right, or how would you handle it?
Dr. Gurbel: We've advised investigations looking at personalized antiplatelet therapy. The amazing paradox in medicine we practice today is a "one size fits all" mentality. And we administer the two most important drugs, aspirin and clopidogrel, without any assessment of whether these agents are actually effective. Many years ago, we described response variability to clopidogrel in 2003 in a Circulation paper and we met a lot of resistance to this concept of resistance.
Dr. Hutter: So what would you do?
Dr. Gurbel: Right now, there are no guidelines to recommend uniform measurement of what...
Dr. Hutter: I'm asking what you would tell us to do.
Dr. Gurbel: What I would tell you is to treat patients according to the guidelines until we have definitive large-scale studies documenting the efficacy of point-of-care assessment of platelet function.
Dr. Hutter: Would you all kind of think that we ought to start getting beyond this one-size-fits-all approach somehow? What about point-of-care assays? There is a device where you can get information whether or not there is adequate platelet response to clopidogrel. It's called VerifyNow (Accumetrics, San Diego) (Slide 3) and it works within minutes. Is that not correct, Gilles?
(Enlarge Image)
Slide 3.
VerifyNow P2Y12 Point-of-Care Assay
Dr. Montalescot: Just 3 minutes to get a response, yeah.
Dr. Hutter: You make a good point, Paul, that we need some outcome studies, but in the meantime we have to make clinical decisions. And, of course, most of the guidelines are based on judgment anyhow. So, what are we to do?
Dr. Gurbel: The issue would be what do you do with the data that you have? How often will an increased dose work? For example, you have low inhibition or high in-treatment platelet reactivity on clopidogrel. What do you do with that? Where are the data that would support a higher dose of clopidogrel? We don't have those data either.
Dr. Sabatine: There are two issues there. As Paul pointed out there is platelet function testing and you can test people and find that they have a suboptimal response defined in a variety of ways. Paul has very nicely shown that you can give higher doses and that tends to move up your degree of inhibition.
Dr. Hutter: It does work in some people, right?
Dr. Gurbel: Yes, but the important point is that in some people it doesn't work and it may be associated with side effects.
Dr. Hutter: What are the side effects?
Dr. Montalescot: Potentially, bleeding and joint pain. In patients who are resistant to clopidogrel with clearly high platelet reactivity on treatment, we'll increase the dose: 2 pills, 3 pills, 4 pills a day. And we have some effect on the platelets side but we have also gastrointestinal side effects or joint pain, for example, and this is probably due to the excess of phenotype metabolizer accumulating. And this is not good. The patients do not like it, and clearly we would need something else and maybe a different drug, which is what we have.
Dr. Hutter: You guys are making a very good point. You know, "Hey, that's kind of simplistic thinking, Dolph, I mean you can't just test it and give more. It might not work, and it might cause some harm." Right? So I guess what we need are some good studies to look at that and, Gilles, you're running a study to look at that specifically?
Dr. Montalescot: Yes, the Artic study; 2,500 patients are being randomized in the cath lab at the time of stent implantation and the only condition is using the assay test (monitoring arm) or not using the test (conventional arm). (Editor's note: For information, go to http://clinicaltrials.gov/archive/NCT00827411/2009_01_21.) We test aspirin, we test clopidogrel, and we give information to the physicians.
Dr. Hutter: You allow the physician to make a decision because Paul's not sure what to do with it.
Dr. Montalescot: Yeah.
Dr. Gurbel: In my heart I'm sure what to do with it, but in practice for the general interventionalist I would say we're still in uncharted waters here. And we should be very cautious.
Dr. Hutter: I understand. So, in the study (ARCTIC) then what? You give it to the physician, what does the physician do?
Dr. Montalescot: There are recommendations. For example, in patients resistant to clopidogrel, do you use IIb/IIIa inhibitors in the cath lab because even if you reload the patient with clopidogrel you need to take some time to get this new load of clopidogrel. For aspirin (resistance) we would reload the patient with aspirin and we're testing the patients 2 weeks later...
Dr. Gurbel: There are randomized dta from one study to suggest that if you are non-responsive to clopidogrel by a point-of-care test, administration of tirofiban showed a reduction in periprocedural events (Slide 4). But this was one study, the numbers are not large, but it makes physiologic sense. The IIb/IIIa inhibitor attenuates platelet aggregation by a separate mechanism.
(Enlarge Image)
Slide 4.
3T/2R: Primary Endpoint at 48 Hours
Dr. Hutter: Just replacing an ineffective one with an effective one.
Dr. Gurbel: Right.
Dr. Sabatine: Another study has come out indicating that platelet function testing and genotyping both wind up being independent predictors of adverse outcomes.
Dr. Hutter: What about genotyping? It can be done faster and faster. Marc, what do you think?
Dr. Sabatine: There are devices now where if you have the DNA you can do the genotyping in the course of a couple of hours, but there's still not a point-of-care device that would be suitable for the cath lab.
But that may change as we get not only the variants that are important for clopidogrel metabolism, but also other medications. We give statins and potentially other medications where genotyping might be useful, so you might have a panel of SNPs that you might check in your cardiovascular patients, either when you start caring for them and/or when they get admitted to the hospital.
Dr. Hutter: Do think it might eventually be cost effective to do that?
Dr. Sabatine: The cost for genotyping in general is going down and I think that won't be an issue. Paul raises the issue, what would we do with the information? We need those studies as well to know, should we treat people differently? I think Gilles is getting genetic data in his ARCTIC Study as well, so we'll be able to combine all that.
Dr. Hutter: So Gilles, in your study, the doctor is going to decide what to do, and probably they're going to use a IIb/IIIa agent. Or is that in part of the protocol? Is that their decision?
Dr. Montalescot: That's part of this protocol, but what we see now is that things are going so fast that many cath labs are using an Accumetrics device so they can monitor patients and make decisions already. But we need a study…
Dr. Hutter: Marc and I were talking about how we need these studies in America, but we aren't set up to do it because it is not the standard of care as you point out, Paul. We've got that great study coming along and there is no reason you can't use the assay. You might say, "Well, let's go ahead and add a IIb/IIIa." Further down the road when you guys are getting all this information, what about new drugs? Are there drugs that bypass this pathway and then we don't have to worry about this?
Dr. Gurbel: The question is: does everyone need a new P2Y12 inhibitor? Or couldn't we selectively administer these drugs to the patients who have high platelet reactivity on the standard workhorse agent, clopidogrel? This raises the issue of determining optimization of therapy with the new agents. Instead of blanket therapy to sort out the patients who really need them, maybe it will be done by genotyping the patient before you choose your antiplatelet agent.
Dr. Hutter: Like they do in cancer now.
Dr. Sabatine: That's a very good analogy. Jessica Mega in our group has a paper coming out; we've done the same analysis in patients treated with prasugrel and found that the 2C19 variant does not impact the pharmacokinetics, the pharmacodynamics, or the clinical outcomes. So as we think about what drugs we might use, the genotyping may start pointing us in one direction versus the other. And there are other compounds that don't even require the CYP450 pathway.
Dr. Hutter: Is it possible that one of these drugs might come along where you don't really need genotyping because everybody responds the same way, or do you think that all patients are going to have some gene variabilities in terms of how they metabolize any particular drug?
Dr. Sabatine: I think there will be differences from drug to drug.
Dr. Gurbel: But if you look at the source of the variability to find pyridines that reside within the liver, with direct acting P2Y12 inhibitors there is no effective polymorphism in the liver. And up to this point in time we don't know of any effect of a P2Y12 polymorphism that affects thienopyridine response or direct acting inhibitor response.
Dr. Hutter: We've still got a lot to learn. Meanwhile, this is entirely independent of aspirin, isn't it? Aspirin has its own set of responders and non-responders. There are some aspirin-resistant people also. And that's another point-of-care study that is being done. What we're talking about is only clopidogrel so far, and not any other agents.
When do you think the ARCTIC study will be out?
Dr. Montalescot: We need one more year.
Dr. Hutter: And maybe we'll get some studies going in the United States in the meantime. Well, thank you all very much. It's a very up-to-date discussion and a very clinically important problem - 30% of the people. Wow! That's something.
And thank you for joining us. I'm Dolph Hutter.